tbuckley/cabot-search huggingface dataset:
BID expression determines the apoptotic fate of cancer cells after abrogation of the spindle assembly checkpoint by AURKB or TTK inhibitors
Authors: Jordi Bertran-Alamillo, Ana Giménez-Capitán, Ruth Román, Sara Talbot, Rebecca Whiteley, Nicolas Floc’h, Elizabeth Martínez-Pérez, Matthew J. Martin, Paul D. Smith, Ivana Sullivan, Mikkel G. Terp, Jamal Saeh, Cristina Marino-Buslje, Giulia Fabbri, Grace Guo, Man Xu, Cristian Tornador, Andrés Aguilar-Hernández, Noemí Reguart, Henrik J. Ditzel, Alejandro Martínez-Bueno, Núria Nabau-Moretó, Amaya Gascó, Rafael Rosell, J. Elizabeth Pease, Urszula M. Polanska, Jon Travers, Jelena Urosevic, Miguel A. Molina-Vila
Journal: Molecular Cancer (2023)

Drugs targeting the spindle assembly checkpoint (SAC), such as inhibitors of Aurora kinase B (AURKB) and dual specific protein kinase TTK, are in different stages of clinical development. However, cell response to SAC abrogation is poorly understood and there are no markers for patient selection.A panel of 53 tumor cell lines of different origins was used. The effects of drugs were analyzed by MTT and flow cytometry. Copy number status was determined by FISH and Q-PCR; mRNA expression by nCounter and RT-Q-PCR and protein expression by Western blotting. CRISPR-Cas9 technology was used for gene knock-out (KO) and a doxycycline-inducible pTRIPZ vector for ectopic expression. Finally, in vivo experiments were performed by implanting cultured cells or fragments of tumors into immunodeficient mice.Tumor cells and patient-derived xenografts (PDXs) sensitive to AURKB and TTK inhibitors consistently showed high expression levels of BH3-interacting domain death agonist (BID), while cell lines and PDXs with low BID were uniformly resistant. Gene silencing rendered BID-overexpressing cells insensitive to SAC abrogation while ectopic BID expression in BID-low cells significantly increased sensitivity. SAC abrogation induced activation of CASP-2, leading to cleavage of CASP-3 and extensive cell death only in presence of high levels of BID. Finally, a prevalence study revealed high BID mRNA in 6% of human solid tumors.The fate of tumor cells after SAC abrogation is driven by an AURKB/ CASP-2 signaling mechanism, regulated by BID levels. Our results pave the way to clinically explore SAC-targeting drugs in tumors with high BID expression.
Integrated multiomic analysis and high‐throughput screening reveal potential gene targets and synergetic drug combinations for osteosarcoma therapy
Authors: Wenchao Zhang, Lin Qi, Zhongyue Liu, Shasha He, Cheng‐zhi Wang, Ying Wu, Lianbin Han, Zhenxin Liu, Zheng Fu, Chao Tu, Zhihong Li
Journal: MedComm (2023)

Although great advances have been made over the past decades, therapeutics for osteosarcoma are quite limited. We performed long-read RNA sequencing and tandem mass tag (TMT)-based quantitative proteome on osteosarcoma and the adjacent normal tissues, next-generation sequencing (NGS) on paired osteosarcoma samples before and after neoadjuvant chemotherapy (NACT), and high-throughput drug combination screen on osteosarcoma cell lines. Single-cell RNA sequencing data were analyzed to reveal the heterogeneity of potential therapeutic target genes. Additionally, we clarified the synergistic mechanisms of doxorubicin (DOX) and HDACs inhibitors for osteosarcoma treatment. Consequently, we identified 2535 osteosarcoma-specific genes and several alternative splicing (AS) events with osteosarcoma specificity and/or patient heterogeneity. Hundreds of potential therapeutic targets were identified among them, which showed the core regulatory roles in osteosarcoma. We also identified 215 inhibitory drugs and 236 synergistic drug combinations for osteosarcoma treatment. More interestingly, the multiomic analysis pointed out the pivotal role of HDAC1 and TOP2A in osteosarcoma. HDAC inhibitors synergized with DOX to suppress osteosarcoma both in vitro and in vivo. Mechanistically, HDAC inhibitors synergized with DOX by downregulating SP1 to transcriptionally modulate TOP2A expression. This study provided a comprehensive view of molecular features, therapeutic targets, and synergistic drug combinations for osteosarcoma.
Matrix stiffness‐induced α‐tubulin acetylation is required for skin fibrosis formation through activation of Yes‐associated protein
Authors: Dongsheng Wen, Ya Gao, Yangdan Liu, Chiakang Ho, Jiaming Sun, Lu Huang, Yuxin Liu, Qingfeng Li, Yifan Zhang
Journal: MedComm (2023)

Skin fibrosis, a pathological process featured by fibroblast activation and extracellular matrix (ECM) deposition, makes a significant contribution to morbidity. Studies have identified biomechanics as the central element in the complex network of fibrogenesis that drives the profibrotic feedback loop. In this study, we found that the acetylation of α-tubulin at lysine 40 (K40) was augmented in fibrotic skin tissues. Further analysis showed that α-tubulin acetylation is required for fibroblast activation, including contraction, migration, and ECM deposition. More importantly, we revealed that biomechanics-induced upregulation of K40 acetylation promotes fibrosis by mediating mechanosensitive Yes-associated protein S127 dephosphorylation and its cytoplasm nucleus shuttle. Furthermore, we demonstrated that the knockdown of α-tubulin acetyltransferase 1 could rescue the K40 acetylation upregulation caused by increased matrix rigidity and ameliorate skin fibrosis both in vivo and in vitro. Herein, we highlight the critical role of α-tubulin acetylation in matrix stiffness-induced skin fibrosis and clarify a possible molecular mechanism. Our research suggests α-tubulin acetylation as a potential target for drug design and therapeutic intervention.
CSF MTBR-tau243 is a specific biomarker of tau tangle pathology in Alzheimer’s disease
Authors: Kanta Horie, Gemma Salvadó, Nicolas R. Barthélemy, Shorena Janelidze, Yan Li, Yingxin He, Benjamin Saef, Charles D. Chen, Hong Jiang, Olof Strandberg, Alexa Pichet Binette, Sebastian Palmqvist, Chihiro Sato, Pallavi Sachdev, Akihiko Koyama, Brian A. Gordon, Tammie L. S. Benzinger, David M. Holtzman, John C. Morris, Niklas Mattsson-Carlgren, Erik Stomrud, Rik Ossenkoppele, Suzanne E. Schindler, Oskar Hansson, Randall J. Bateman
Journal: Nature Medicine (2023)

Abstract Aggregated insoluble tau is one of two defining features of Alzheimer’s disease. Because clinical symptoms are strongly correlated with tau aggregates, drug development and clinical diagnosis need cost-effective and accessible specific fluid biomarkers of tau aggregates; however, recent studies suggest that the fluid biomarkers currently available cannot specifically track tau aggregates. We show that the microtubule-binding region (MTBR) of tau containing the residue 243 (MTBR-tau243) is a new cerebrospinal fluid (CSF) biomarker specific for insoluble tau aggregates and compared it to multiple other phosphorylated tau measures (p-tau181, p-tau205, p-tau217 and p-tau231) in two independent cohorts (BioFINDER-2, n = 448; and Knight Alzheimer Disease Research Center, n = 219). MTBR-tau243 was most strongly associated with tau-positron emission tomography (PET) and cognition, whereas showing the lowest association with amyloid-PET. In combination with p-tau205, MTBR-tau243 explained most of the total variance in tau-PET burden (0.58 ≤ R 2 ≤ 0.75) and the performance in predicting cognitive measures (0.34 ≤ R 2 ≤ 0.48) approached that of tau-PET (0.44 ≤ R 2 ≤ 0.52). MTBR-tau243 levels longitudinally increased with insoluble tau aggregates, unlike CSF p-tau species. CSF MTBR-tau243 is a specific biomarker of tau aggregate pathology, which may be utilized in interventional trials and in the diagnosis of patients. Based on these findings, we propose to revise the A/T/(N) criteria to include MTBR-tau243 as representing insoluble tau aggregates (‘T’).
Antipsychotic drug efficacy correlates with the modulation of D1 rather than D2 receptor-expressing striatal projection neurons
Authors: Seongsik Yun, Ben Yang, Justin D. Anair, Madison M. Martin, Stefan W. Fleps, Arin Pamukcu, Nai-Hsing Yeh, Anis Contractor, Ann Kennedy, Jones G. Parker
Journal: Nature Neuroscience (2023)
Integrating spatial and single-nucleus transcriptomic data elucidates microglial-specific responses in female cynomolgus macaques with depressive-like behaviors
Authors: Jing Wu, Yifan Li, Yu Huang, Lanxiang Liu, Hanping Zhang, Corina Nagy, Xunmin Tan, Ke Cheng, Yiyun Liu, Juncai Pu, Haiyang Wang, Qingyuan Wu, Seth W. Perry, Gustavo Turecki, Ma-Li Wong, Julio Licinio, Peng Zheng, Peng Xie
Journal: Nature Neuroscience (2023)
Interpreting the retinal neural code for natural scenes: From computations to neurons
Authors: Niru Maheswaranathan, Lane T. McIntosh, Hidenori Tanaka, Satchel Grant, David B. Kastner, Joshua B. Melander, Aran Nayebi, Luke E. Brezovec, Julia H. Wang, Surya Ganguli, Stephen A. Baccus
Journal: Neuron (2023)

Understanding the circuit mechanisms of the visual code for natural scenes is a central goal of sensory neuroscience. We show that a three-layer network model predicts retinal natural scene responses with an accuracy nearing experimental limits. The model's internal structure is interpretable, as interneurons recorded separately and not modeled directly are highly correlated with model interneurons. Models fitted only to natural scenes reproduce a diverse set of phenomena related to motion encoding, adaptation, and predictive coding, establishing their ethological relevance to natural visual computation. A new approach decomposes the computations of model ganglion cells into the contributions of model interneurons, allowing automatic generation of new hypotheses for how interneurons with different spatiotemporal responses are combined to generate retinal computations, including predictive phenomena currently lacking an explanation. Our results demonstrate a unified and general approach to study the circuit mechanisms of ethological retinal computations under natural visual scenes.
A distinct stimulatory cDC1 subpopulation amplifies CD8+ T cell responses in tumors for protective anti-cancer immunity
Authors: Philippa Meiser, Moritz A. Knolle, Anna Hirschberger, Gustavo P. de Almeida, Felix Bayerl, Sebastian Lacher, Anna-Marie Pedde, Sophie Flommersfeld, Julian Hönninger, Leonhard Stark, Fabian Stögbauer, Martina Anton, Markus Wirth, Dirk Wohlleber, Katja Steiger, Veit R. Buchholz, Barbara Wollenberg, Christina E. Zielinski, Rickmer Braren, Daniel Rueckert, Percy A. Knolle, Georgios Kaissis, Jan P. Böttcher
Journal: Cancer Cell (2023)

Type 1 conventional dendritic cells (cDC1) can support T cell responses within tumors but whether this determines protective versus ineffective anti-cancer immunity is poorly understood. Here, we use imaging-based deep learning to identify intratumoral cDC1-CD8+ T cell clustering as a unique feature of protective anti-cancer immunity. These clusters form selectively in stromal tumor regions and constitute niches in which cDC1 activate TCF1+ stem-like CD8+ T cells. We identify a distinct population of immunostimulatory CCR7neg cDC1 that produce CXCL9 to promote cluster formation and cross-present tumor antigens within these niches, which is required for intratumoral CD8+ T cell differentiation and expansion and promotes cancer immune control. Similarly, in human cancers, CCR7neg cDC1 interact with CD8+ T cells in clusters and are associated with patient survival. Our findings reveal an intratumoral phase of the anti-cancer T cell response orchestrated by tumor-residing cDC1 that determines protective versus ineffective immunity and could be exploited for cancer therapy.
Gut microbiota modulate distal symmetric polyneuropathy in patients with diabetes
Authors: Junpeng Yang, Xueli Yang, Guojun Wu, Fenglian Huang, Xiaoyang Shi, Wei Wei, Yingchao Zhang, Haihui Zhang, Lina Cheng, Lu Yu, Jing Shang, Yinghua Lv, Xiaobing Wang, Rui Zhai, Pan Li, Bota Cui, Yuanyuan Fang, Xinru Deng, Shasha Tang, Limin Wang, Qian Yuan, Liping Zhao, Faming Zhang, Chenhong Zhang, Huijuan Yuan
Journal: Cell Metabolism (2023)

The pathogenic mechanisms underlying distal symmetric polyneuropathy (DSPN), a common neuropathy in patients with diabetes mellitus (DM), are not fully understood. Here, we discover that the gut microbiota from patients with DSPN can induce a phenotype exhibiting more severe peripheral neuropathy in db/db mice. In a randomized, double-blind, and placebo-controlled trial (ChiCTR1800017257), compared to 10 patients who received placebo, DSPN was significantly alleviated in the 22 patients who received fecal microbiota transplants from healthy donors, independent of glycemic control. The gut bacterial genomes that correlated with the Toronto Clinical Scoring System (TCSS) score were organized in two competing guilds. Increased guild 1, which had higher capacity in butyrate production, and decreased guild 2, which harbored more genes in synthetic pathway of endotoxin, were associated with improved gut barrier integrity and decreased proinflammatory cytokine levels. Moreover, matched enterotype between transplants and recipients showed better therapeutic efficacy with more enriched guild 1 and suppressed guild 2. Thus, changes in these two competing guilds may play a causative role in DSPN and have the potential for therapeutic targeting.
Tissue factor is a critical regulator of radiation therapy-induced glioblastoma remodeling
Authors: Hye-Min Jeon, Jeong-Yub Kim, Hee Jin Cho, Won Jun Lee, Dayna Nguyen, Sung Soo Kim, Young Taek Oh, Hee-Jin Kim, Chan-Woong Jung, Gonzalo Pinero, Tanvi Joshi, Dolores Hambardzumyan, Takuya Sakaguchi, Christopher G. Hubert, Thomas M. McIntyre, Howard A. Fine, Candece L. Gladson, Bingcheng Wang, Benjamin W. Purow, Jong Bae Park, Myung Jin Park, Do-Hyun Nam, Jeongwu Lee
Journal: Cancer Cell (2023)

Radiation therapy (RT) provides therapeutic benefits for patients with glioblastoma (GBM), but inevitably induces poorly understood global changes in GBM and its microenvironment (TME) that promote radio-resistance and recurrence. Through a cell surface marker screen, we identified that CD142 (tissue factor or F3) is robustly induced in the senescence-associated β-galactosidase (SA-βGal)-positive GBM cells after irradiation. F3 promotes clonal expansion of irradiated SA-βGal+ GBM cells and orchestrates oncogenic TME remodeling by activating both tumor-autonomous signaling and extrinsic coagulation pathways. Intratumoral F3 signaling induces a mesenchymal-like cell state transition and elevated chemokine secretion. Simultaneously, F3-mediated focal hypercoagulation states lead to activation of tumor-associated macrophages (TAMs) and extracellular matrix (ECM) remodeling. A newly developed F3-targeting agent potently inhibits the aforementioned oncogenic events and impedes tumor relapse in vivo. These findings support F3 as a critical regulator for therapeutic resistance and oncogenic senescence in GBM, opening potential therapeutic avenues.
Minimum resolution requirements of digital pathology images for accurate classification
Authors: Lydia Neary-Zajiczek, Linas Beresna, Benjamin Razavi, Vijay Pawar, Michael Shaw, Danail Stoyanov
Journal: Medical Image Analysis (2023)

Digitization of pathology has been proposed as an essential mitigation strategy for the severe staffing crisis facing most pathology departments. Despite its benefits, several barriers have prevented widespread adoption of digital workflows, including cost and pathologist reluctance due to subjective image quality concerns. In this work, we quantitatively determine the minimum image quality requirements for binary classification of histopathology images of breast tissue in terms of spatial and sampling resolution. We train an ensemble of deep learning classifier models on publicly available datasets to obtain a baseline accuracy and computationally degrade these images according to our derived theoretical model to identify the minimum resolution necessary for acceptable diagnostic accuracy. Our results show that images can be degraded significantly below the resolution of most commercial whole-slide imaging systems while maintaining reasonable accuracy, demonstrating that macroscopic features are sufficient for binary classification of stained breast tissue. A rapid low-cost imaging system capable of identifying healthy tissue not requiring human assessment could serve as a triage system for reducing caseloads and alleviating the significant strain on the current workforce.
Oral difelikefalin reduces moderate to severe pruritus and expression of pruritic and inflammatory biomarkers in subjects with atopic dermatitis
Authors: Emma Guttman-Yassky, Paola Facheris, Joel Correa Da Rosa, Camille Rothenberg-Lausell, Ester del Duca, Eden David, Yeriel Estrada, Ying Liu, Swaroop Bose, Mashkura Chowdhury, Catherine Munera, Joana Goncalves, Kristine Nograles, Brian S. Kim, Mark Lebwohl
Journal: Journal of Allergy and Clinical Immunology (2023)

Pruritus is the most common and burdensome symptom of atopic dermatitis (AD). Pruritus-targeted treatments in AD are lacking, particularly for patients with milder skin disease.We sought to evaluate the impact of the selective κ-opioid receptor agonist difelikefalin (DFK) on pruritus intensity and pruritus- and immune-related biomarkers in subjects with moderate to severe AD-related pruritus.A phase 2 clinical trial investigated the efficacy and safety of oral DFK 0.25, 0.5, and 1.0 mg in subjects with moderate to severe AD-related pruritus. A biomarker substudy evaluated the effects of DFK on the expression of pruritus, TH2-associated genes, and skin barrier-related genes.In the clinical trial (N = 401), all DFK doses reduced itch versus placebo; however, the results were not statistically significant at week 12. In a subgroup of subjects in the trial with mild to moderate skin inflammation and moderate to severe itch (itch-dominant AD phenotype), DFK reduced itch at week 12 versus placebo. In the biomarker substudy, DFK downregulated the expression of key pruritus-related genes (eg, IL-31 and TRPV1) and the AD phenotype (eg, CCL17). Gene set variation analysis confirmed that DFK, but not placebo, downregulated pruritus-related genes and TH2 pathways. DFK improved skin barrier integrity markers and upregulated the expression of claudins and lipid metabolism-associated genes (eg, SEC14L6, ELOVL3, CYP1A2, and AKR1D1).DFK treatment reduced itch in subjects with moderate to severe AD-related pruritus, particularly those with an "itch-dominant" AD phenotype, and had an impact on the expression of pruritus, TH2-associated genes, and skin barrier-related genes. DFK is a promising therapy for AD-related pruritus; further clinical studies are warranted.
Endoscopic removal of an extraluminal gastrointestinal stromal tumor recurrence located on the surgical stapler line at gastroesophageal junction
Authors: Thomas Thomaidis, An-Yi Xiang, Orestis Lyros, Ilias Athanasiadis, George Kallimanis, Dimitris Papaioannou, Ping-Hong Zhou
Journal: Endoscopy (2023)

A 58-year-old man was diagnosed 4 years ago with a 9-cm gastrointestinal stromal tumor (GIST) of the gastric fundus. Under neoadjuvant treatment with imatinib, the GIST was substantially reduced in size and subsequently removed via laparoscopic fundus resection. Despite adjuvant treatment, a recurrence appeared 3 years later at the surgical site on the staple line ([Fig. 1 a]). Owing to a secondary mutation on exon 18 of c-kit, treatment with ripretinib was initiated [1], under which the GIST reduced in size, from 3 cm to 2.3 cm. Subsequently, surgical removal was proposed but the patient preferred an endoscopic approach.
Endoscopic submucosal dissection for early gastric cancer, using a disposable endoscope
Authors: Kenichiro Okimoto, Tomoaki Matsumura, Mai Fujie, Naoki Akizue, Keisuke Matsusaka, Jun Kato, Naoya Kato
Journal: Endoscopy (2023)

The environment in reusable endoscopes is conducive to bacterial growth [1] [2] because of difficult-to-clean areas, deterioration with reprocessing, and surface abrasion. Hence, the risk of cross-infection has been reported [3]. Single-use endoscopes can solve these problems. Diagnostic esophagogastroduodenoscopy using a novel sterile single-use disposable endoscope (Ambu aScope Gastro; Ambu, Ballerup, Denmark) has been reported in recent years ([Fig. 1]) [4].
A loop cutter is an ideal gripper for endoscopic removal of press-through-package sheets
Authors: Yuji Ino, Masafumi Kitamura, Yoshie Nomoto, Chihiro Iwashita, Yoshimasa Miura, Tomonori Yano, Hironori Yamamoto
Journal: Endoscopy (2023)

A press-through package (PTP) sheet is sometimes accidentally swallowed [1]. PTP sheets have sharp edges ([Fig. 1]) and may cause mucosal damage and/or perforation to the gastrointestinal tract [2] [3]. Thus, ingested PTP sheets should be removed endoscopically as soon as possible. Several methods have been reported using hoods and covers to prevent mucosal damage during removal [4] [5]. However, a firm grip on the PTP sheet is necessary for successful removal. Grasping forceps or a snare are commonly used as grasping devices but can often fail because the PTP is slippery with saliva and the working space is insufficient for snaring. To address this, we used a Loop Cutter (FS-5L-1; Olympus, Tokyo, Japan), whose teeth can penetrate the PTP plastic sheet to secure a firm grip. The Loop Cutter's strong grip allows the PTP to be easily removed.
Co-targeting RANK pathway treats and prevents acquired resistance to CDK4/6 inhibitors in luminal breast cancer
Authors: Inês Gomes, Lina M. Gallego-Paez, Maria Jiménez, Patricia G. Santamaria, André Mansinho, Rita Sousa, Catarina Abreu, Eva González Suárez, Luis Costa, Sandra Casimiro
Journal: Cell Reports Medicine (2023)

The combination of endocrine therapy (ET) and cyclin-dependent kinase 4/6 (CDK4/6) inhibitors (CDK4/6i) was a hallmark in metastatic luminal breast cancer (BC). However, intrinsic and acquired resistance affects long-term efficacy. Here, we study the role of the receptor activator of nuclear factor-κB (RANK) pathway in CDK4/6i resistance. We find that RANK overexpression in luminal BC is associated with intrinsic resistance to CDK4/6i, both in vitro and in mouse xenografts, and decreased proliferation rate and chronic interferon (IFN) γ response are highlighted as resistance drivers. Gene expression data from the NeoPalAna CDK4/6i clinical trial, and studies with palbociclib-resistant cell lines, show that RANK is upregulated after treatment with CDK4/6i, supporting a role in acquired resistance. Our study shows that RANK ligand (RANKL) inhibitors can restore sensitivity to CDK4/6i and prevent acquired resistance. On the basis of these findings, we conclude that pharmacological inhibition of the RANK pathway through RANKL blocking could represent an add-on to ET + CDK4/6i, warranting further clinical studies.